Alterations of the norepinephrine (NE) neurotransmitter pathway within the central nervous system have been implicated in a number of significant mental health disorders, including depression, attention deficit disorder, and Alzheimer's Disease, in addition to the neuropathological conditions associated with aging and psychostimulant drug abuse. The norepinephrine transporter (NET) is an integral membrane protein responsible for transport of NE into the presynaptic terminal. The density of cell surfaced expressed NET is considered a marker for the number or integrity of NE terminals where NET levels vary across brain structures. The quantitative determinations of NET density in discrete cerebral regions of primate brain using dynamic positron emission tomography (PET) imaging holds tremendous clinical promise. However, an efficacious NET PET imaging agent for primate brain has yet to be identified. Our long-term objective is to provide the clinical PET imaging community an efficacious human cerebral NET imaging tracer for: i) quantitative diagnoses of major neuropathological and neuropsychiatric disorders where regional cerebral NET densities are altered as a function of CNS disease state;and ii) quantitative assessments of therapies which influence cerebral NET protein biomarker concentrations. The purpose of this R21/R33 investigation is to satisfy the critical unmet NET tracer need. The investigation will afford candidate NET PET imaging agents with unique in vitro structure- activity relationships and efficacious in vivo pharmacokinetic imaging profiles suitable for quantifying NET density in primate brain. We will satisfy the milestones of the R21 portion of the investigation by medicinal chemistry, radiopharmaceutical and PET imaging screening studies, which will identify at least two structurally novel, potent and selective NET tracers possessing appropriate regional cerebral activity distributions correlated to known NET density profiles and cerebral tissue pharmacokinetic properties suitable for determining NET densities by kinetic analyses. The R33 development segment of the investigation will delineate one (or more) efficacious cerebral NET PET imaging radioligand as a candidate tracer(s) by in depth quantitative PET imaging experiments, followed by tracer toxicological-safety determinations and the FDA approval of an exploratory investigation new drug (eIND) application for future human clinical evaluations. The investigation will further evaluate several contemporary hypotheses encompassing radioligand discovery, tracer development and quantitative PET imaging of primate brain. PUBLIC HEALTH RELEVANCE: Alterations of the norepinephrine (NE) neurotransmitter pathway within central nervous system have been implicated in a number of significant mental health disorders and debilitating neuropathological conditions. The relevance of the investigation is to afford novel positron emission tomography (PET) brain imaging agents that will be suitable for the clinical assessment of the integrity of NE system in live primate brain, through their interactions with the norepinephrine transporter protein. Since efficacious PET imaging tracers for the NE system have yet to be described, the investigation will satisfy this critical unmet need.